1. Field of the Invention
The present invention relates to pili obtained from Mycobacterium tuberculosis, methods of producing the pili and the use of the pili for inducing an immune response against Mycobacterium tuberculosis. The present invention also provides proteins and peptides which are constituents of the pili. Antibodies which bind to the pili are also provided.
2. Description of the Background
Mycobacterium tuberculosis is the bacterial agent responsible for human pulmonary tuberculosis (TB). Almost one third of the world's population suffers from this infectious disease. The M. tuberculosis bacillus is highly infectious and is spread by aerosols from infected individuals with active pulmonary disease. Over three million people die yearly from tuberculosis, the largest single infectious cause of mortality worldwide. Tuberculosis is still a persistent health problem in the U.S.A. due in part to the human immunodeficiency virus (AIDS) epidemic. AIDS patients are highly susceptible to infection with M. tuberculosis and other non-tuberculosis mycobacteria that seldom infect individuals with intact immune systems. For many bacterial pathogens, the ability to produce proteinaceous adhesins in the form of hair-like structures, called pili, are an important pathogenic attribute since they mediate close interaction and colonization with host cells. Due to the critical role pili play in the establishment of the infectious process and their immunogenecity, pili are considered good candidates for vaccine development.
Although tuberculosis is now recognized as a major public health problem nationally and internationally, there is a need for more information on the basic molecular mechanisms of M. tuberculosis pathogenesis and the mechanisms of drug resistance and immunity to this pathogen. Key to tuberculosis pathogenesis is the ability of the bacilli to adhere and enter macrophages and possibly other host cell types, to resist killing, and to replicate in these intracellular sites. The specific molecular mechanisms M. tuberculosis uses in these processes are unknown. But the recent DNA sequencing and annotation of the laboratory strain M. tuberculosis H37Rv and the clinical isolate CDC1551 genomes have added much to our general knowledge of the genetics of this microbial pathogen.
Adherence to host tissues is an essential and complex first stage for bacterial colonization for the establishment of bacterial infectious disease. In many cases, adherence is mediated by one or more adhesins that can act simultaneously or in distinct steps of an infectious process. Adhesins, in the form of pili or outer membranes proteins, may mediate direct or indirect binding to host cells. Therefore, blocking the interaction of piliated bacteria with host cells through specific anti-pili antibodies represents a feasible strategy for developing an immunoprophylaxis regimen. A great deal of information is available in terms of the interaction and trafficking of M. tuberculosis within macrophages of the immune system. It is reasonable to presume that the bacteria are able to express surface molecules devoted to the specific recognition of unique or common receptor components present on target tissues. Nevertheless, the mechanisms underlying the adherence properties of M. tuberculosis to the first line of epithelial cells before interacting with professional phagocytes are just beginning to be unraveled. Analysis of the genome sequence of M. tuberculosis has revealed various genes coding for putative adhesins and invasins, although their roles in M. tuberculosis pathogenesis remain to be determined.